1. Field of the Invention
The present invention relates to coactivators of hormone and growth factor activity in cancer cells and, specifically, to isoforms of the coactivator amplified in breast. In particular, the invention relates to compositions, diagnostic kits and methods for utilizing coactivator isoforms for the diagnosis, treatment and prevention of cancers such as breast cancer.
2. Description of the Background
Ligands such as estrogen and progesterone that interact with nuclear receptors regulate gene expression predominantly at the transcriptional level. The ligand-bound receptors interact specifically with DNA and activate transcription by recruiting a preinitiation complex. Although such gene activation was originally thought to be mediated by interaction of the receptors with components of the basal transcriptional machinery (1-6), a variety of screening techniques has identified a family of receptor-interacting proteins known as nuclear receptor coactivators (7-11). A common characteristic of this superfamily of proteins is that, when overexpressed in the presence of nuclear receptors, they potentiate ligand induction of transcription (12, 13). The related p160 group of coactivators, which include steroid receptor coactivators (Src-1), Src-2, and Src-3 (which is also known as AIB1, ACTR, RAC3, TRAM-1, and p/CIP) (14-20), possess several similar structural features including a receptor interaction domain (RID), a bHLH (basic helix-loop-helix)PAS (Per-Arnt-Sim homology) dimerization domain, and a CBP interaction domain (CID) (13). Coactivators are thought to function as bridges between nuclear receptors and either other coactivators or the basal transcriptional machinery (13). It was discovered that coactivators possess a histone acetylase domain (15, 21-24), which suggests that these proteins also might serve to regulate chromatin structure.
A portion of human chromosome 20 q that is frequently amplified in breast cancer contains the gene for the nuclear coactivator AIB1 (amplified in breast cancer 1) (25). The AIB1 gene is amplified in five to ten percent of breast cancers and the abundance of the corresponding mRNA and protein is increased in 30-50% of breast tumors and also breast cancer cell lines (14, 25-27). It has recently been shown that AIB1 binds directly to ER (28) and that AIB1 is rate-limiting for estrogen-induced growth of MCF-7 cells (29). However, the overall role of AIB1 for breast tumorigenesis has not been clear since AIB1 potentiates not only the action of estrogen (14, 16) and progesterone (16) receptors, but also that of various other nuclear receptors (9, 15, 17-20) and transcription factors (30, 31). In addition, several splice variants of SRC family members have been described, although the functions of these variants remain unknown (13).